Glycoprotein IIb/IIIa Inhibitors: The Resurgence of Tirofiban Cassidy Harmon, Shawn King, Marintha Short PII: DOI: Reference:

S1537-1891(15)00157-3 doi: 10.1016/j.vph.2015.07.008 VPH 6231

To appear in:

Vascular Pharmacology

Received date: Revised date: Accepted date:

11 May 2015 12 July 2015 13 July 2015

Please cite this article as: Harmon, Cassidy, King, Shawn, Short, Marintha, Glycoprotein IIb/IIIa Inhibitors: The Resurgence of Tirofiban, Vascular Pharmacology (2015), doi: 10.1016/j.vph.2015.07.008

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ACCEPTED MANUSCRIPT Glycoprotein IIb/IIIa Inhibitors: The Resurgence of Tirofiban

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CORRESPONDING AUTHOR: Cassidy Harmon, PharmD Email: [email protected] Telephone: (513)406-2428

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AUTHORS: Shawn King, PharmD Marintha Short, PharmD

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PRONUNCIATION KEY: Abciximab (ab-SIKS-ih-mab) Eptifibatide (ep-ti-FIB-ih-tide) Tirofiban (tye-roe-FYE-ban)

ABSTRACT

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Glycoprotein (GP) IIb/IIIa inhibitors block platelet aggregation, reducing thrombotic events in acute coronary syndrome. They are most often utilized in patients who likely have an intracoronary thrombus. Tirofiban, eptifibatide, and abciximab are the three GP IIb/IIIa inhibitors approved for use in the United States. Each agent has unique pharmacological properties. They all have a rapid onset and are most often utilized in conjunction with heparin. Tirofiban, in particular, fell out of favor due to inferior dosing with its original Food and Drug Administration (FDA) approved indication, but has re-emerged in the market with a high-dose bolus regimen that is considered equally as effective as the FDA approved dosing regimens of other GP IIb/IIIa inhibitors. This review looks at pharmacological properties of all three agents, significant clinical trials associated with their use, and their place in current guidelines.

INTRODUCTION

Glycoprotein (GP) IIb/IIIa inhibitors are a class of agents commonly utilized in the setting of unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), or ST segment elevation myocardial infarction (STEMI). The purpose of these agents is to reduce the rate of thrombotic cardiovascular events, defined as the combined endpoint of death, myocardial infarction (MI), or refractory ischemia/repeat cardiac procedure in this patient population. GP IIb/IIIa inhibitors are used off-label in the setting of STEMI to decrease the incidence of early stent thrombosis after primary percutaneous intervention (PCI). However, none of these agents have a Food and Drug Administration (FDA) approved indication for use in this patient population. Three agents in this drug class are approved in the United States, each with unique characteristics. These include abciximab (ReoPro®), eptifibatide (Integrilin®), and tirofiban (Aggrastat®).

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ACCEPTED MANUSCRIPT GLYCOPROTEIN IIB/IIIA INHIBITORS

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The development of GP IIb/IIIa inhibitors arose from the understanding of a rare autosomal recessive bleeding disorder called Glanzmann’s thrombasthenia (GT), in which a patient is devoid of GP IIb/IIIa receptors. GP IIb/IIIa is a platelet integrin aggregation receptor. When this receptor is stimulated by adenosine diphosphate (ADP), epinephrine, collagen, or thrombin, it becomes activated and binds fibrinogen, von Willebrand factor (vWF), fibronectin, and vitronectin. Fibrinogen causes platelet-platelet interaction and aggregation. Therefore, in GT, without the fibrinogen binding of platelets, bleeding time is significantly prolonged1.

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This GP IIb/IIIa platelet membrane receptor is needed for platelet aggregation which allows for clot formation. It is the most abundant receptor, with about 80,000 copies per platelet, and is expressed on the membranes of platelets and megakaryocytes. The class of medications called GP IIb/IIIa inhibitors work by blocking the final pathway of platelet aggregation, the fibrinogen-mediated crosslinkage of platelets, preventing thrombosis2. The receptors, which are inactive on resting platelets, consist of non-covalently linked heterodimers. As these platelets become activated, this triggers a conformational activation of the receptor. The activated receptors bind fibrinogen, which bridges platelets together inducing platelet aggregation.

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All three commonly utilized GP IIb/IIIa inhibitors traditionally are administered as an intravenous (IV) bolus followed by a continuous infusion, although more recent data shows alternative dosing strategies may be appropriate in conjunction with thienopyridines. While all three agents target the same receptor, they each have distinct pharmacological and structural differences. Abciximab is a larger molecule with a strong affinity for the platelet GP IIb/IIIa receptor. Eptifibatide and tirofiban are smaller molecules with a lesser degree of affinity for the platelet GP IIb/IIIa receptor and shorter duration of action. Tirofiban and eptifibatide have reversible receptor inhibition while abciximab has irreversible receptor inhibition (see table 1)2.

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ACCEPTED MANUSCRIPT Table 1. Comparison of Glycoprotein IIb/IIIa Inhibitors

Abciximab

Brand Name

Integrilin®

Aggrastat®

ReoPro®

Manufacturer

Merck

Medicure Pharma

Structure

Cyclic heptatide

Non-peptide

Molecular weight (kD)

Small molecule (0.832)

Small molecule (0.495)

Affinity (KD)

120 nM

Specific for GPIIb/IIIa Excretion

Yes

Plasma half-life

Eli Lilly Antibody Fab fragment Large molecule (47.6)

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Eptifibatide Tirofiban

5 nM

Renal

Unknown

~2.5 hours

~2 hours

10-30 min

Receptor inhibition Onset of antiplatelet effect Platelet recovery

Reversible

Reversible

Irreversible

Within 20 min

Within 20 min

Within 20 min

Fast (2-4 hours)

Fast (2-4 hours)

Slow (~48 hours)

Storage

Refrigeration required

Room temperature

Refrigeration required

FDA approved indications

ACS and PCI (UA and NSTEMI)

ACS (UA and NSTEMI)

PCI; refractory UA/NSTEMI when PCI is planned within 24 hours

Bolus

Double

Single

Single

Infusion

Up to 18-24 hours Up to18 hours (12 hours minimum)

Yes

No

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Renal

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15 nM

12 hours

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Figure 1. Structure of GP IIb/IIIa Inhibitors

Eptifibatide4

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Abciximab (C6462H9964N1690O2049S48)3

Tirofiban5

The 2012 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for UA/NSTEMI recommend that when an initial conservative strategy is chosen but recurrent ischemia, heart failure, or serious arrhythmias occur, using either a P2Y12 inhibitor (clopidogrel or ticagrelor) or a GP IIb/IIIa inhibitor should be administered in addition to aspirin. These patients are expected to utilize an invasive strategy and undergo diagnostic angiography and PCI. Eptifibatide or tirofiban are preferred agents, while abciximab is recommended only if administered at the time of the PCI. Guidelines recommend all three GPIIb/IIIa inhibitors equally, stating that they are all similar in efficacy in safety with regards to mortality, target vessel revascularization, and bleeding6, 7.

GP IIb/IIIa inhibitors can be effective adjunctive treatment during primary PCI for STEMI or non-ST-segment elevation acute coronary syndrome (NSTE-ACS). NSTE-ACS, as referred to in the 2014 ACC/AHA guidelines, is defined as both UA and NSTEMI. Upon presentation, patients with UA and NSTEMI are 4

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oftentimes indistinguishable and so this category of NSTE-ACS categorizes them together7. Guidelines recommend that in patients undergoing PCI who have been treated with unfractionated heparin (UFH), it is reasonable to administer an IV GP IIb/IIIa inhibitor such as abciximab, eptifibatide, or tirofiban. This recommendation exists regardless of whether the patients are pretreated with clopidogrel. However, for patients who are not pretreated with clopidogrel, the level of evidence is A, while for patients who are pretreated with clopidogrel, the level of evidence is C7-10. The benefits of all of these agents are greater when the patient has not been pretreated with thienopyridines10, 11. In STEMI patients undergoing PCI, abciximab and eptifibatide administered through the IV route have shown similar results with regards to angiographic, electrocardiographic, and clinical outcomes12-15. GP IIb/IIIa inhibitor use in STEMI patients is most common in those with a large anterior myocardial infarction (MI) or those with large thrombus burden. It has been used off-label to bridge a thienopyridine until its full antiplatelet effects are in place. Upstream use of GP IIb/IIIa inhibitors prior to catheterization in patients undergoing PCI, such as in the emergency department or in an ambulance while transporting the patient to a PCI center, is recommended in the STEMI guidelines as a reasonable option for those with intended PCI8. For NSTE-ACS, upstream use of GP IIb/IIIa inhibitors are not recommended in those at low risk for ischemic events or at high risk for bleeding events in those who have already received aspirin and a P2Y12 inhibitor6.

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The 2014 European Society of Cardiology (ESC) guidelines on myocardial revascularization are more conservative with their recommendations for GP IIb/IIIa inhibitors. They recommend that NSTE-ACS patients only receive GP IIb/IIIa inhibitors as bail-out therapy and that pre-treatment with these agents where coronary anatomy is unknown is not recommended. In STEMI patients, GP IIb/IIIa inhibitors can be considered for bail-out or evidence of no-reflow or a thrombotic complication. These guidelines also specify that the upstream use of GP IIb/IIIa inhibitors can be considered in high-risk patients who are being transferred to a primary PCI facility16. Intracoronary administration of these medications was thought to potentially increase the efficacy of primary PCI by resulting in higher concentrations of drug at the site of action than with intravenous administration17. Administration of these agents through the intracoronary route is safe and effective in reducing the infarct size and providing good clinical outcomes, but is no more effective or safe than when given intravenously18, 19. The trials comparing intracoronary versus intravenous administration of GP IIb/IIIa inhibitors during primary PCI in STEMI patients have varied results. The American Heart Association (AHA), and the American College of Cardiology (ACC) noted in the 2011 guidelines for primary PCI that in patients undergoing primary PCI with abciximab, it may be reasonable to administer intracoronary abciximab. This recommendation was not available for other GP IIb/IIIa inhibitors9. The 2014 ESC guidelines on myocardial revascularization do not make any specific recommendations regarding intracoronary administration of GP IIb/IIIa inhibitors20.

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While these agents improve survival and outcomes in certain patient populations, they also put these patients at increased risk of bleeding, including retroperitoneal, pulmonary, and spontaneous gastrointestinal (GI) and/or genitourinary (GU) bleeding. The most serious complications of all GPIIb/IIIa inhibitors are bleeding and thrombocytopenia. Thrombocytopenia is typically immune related caused by antibodies that are directed against neoantigens on GPIIb/IIIa that are exposed on antagonist binding. This is more common with abciximab than with eptifibatide or tirofiban. After stopping the infusion of the small molecule GP IIb/IIIa inhibitors, the receptor blocking activity and bleeding risk subside21, 22.

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Thrombocytopenia with GP IIb/IIIa inhibitors typically occurs within 24 hours of administration, and oftentimes even sooner. Platelets should be monitored in these patients frequently, beginning at baseline prior to inititation of treatment, again 2 to 4 hours after the bolus, and then daily during the infusion. Pseudothrombocytopenia should be ruled out first with a peripheral blood smear. If it is ruled out and platelets are 100,000/microL or less, the GP IIb/IIIa inhibitor should be stopped23. The patient should receive a platelet transfusion if the platelet count falls below 20,000/microL, if there is overt bleeding, or if an emergency invasive procedure required24. Platelets will likely recover within 1 to 5 days with eptifibatide or tirofiban but may take up to 3 days to 2 weeks with abciximab. After a patient experiences thrombocytopenia from a GP IIb/IIIa inhibitor, it is not recommended to rechallenge the patient with that particular agent as it may cause a more severe thrombocytopenia. Administration of an alternative GP IIb/IIIa inhibitor may be possible, however there is a 15 percent cross-reactivity25-29. The use of GP IIb/IIIa inhibitors has declined over the last few years. One reason is because of the HORIZONS-AMI trial which compared heparin plus a GP IIb/IIIa inhibitor to bivalirudin. This trial showed that in patients with STEMI who underwent primary PCI, bivalirudin was associated with improved event-free survival at 30 days with a reduction in rates of major bleeding28. This trial led to the addition of bivalirudin to current ACC/AHA STEMI guidelines8. Another reason for a decrease in usage of GP IIb/IIIa inhibitors is that newer P2Y12 inhibitors (prasugrel and ticagrelor) have a faster and more pronounced antiplatelet effect compared to clopidogrel and are often used as replacements for GP IIb/IIIa inhibitors. However, GP IIb/IIIa inhibitors are sometimes used in practice for bridged platelet inhibition after a loading dose of clopidogrel, prasugrel, or ticagrelor before these P2Y12 inhibitors have full antiplatelet action. Tirofiban is infused for 4 to 6 hours after a clopidogrel load or 2 to 4 hours after a prasugrel or ticagrelor load for bridging, or can be infused for up to 18 hours in high risk cases. The BRIEF-PCI study supports the use of short-term infusions of IIb/IIIa inhibitors instead of infusing the full 18 to 24 hours29. The FABOLOUS PRO Trial compared inhibition of platelet aggregation (IPA) with the use of

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ACCEPTED MANUSCRIPT prasugrel versus a tirofiban bolus with or without a post-bolus short infusion in STEMI patients. Using a high-dose bolus of tirofiban bridged the first 2 hours where prasugrel was associated with suboptimal IPA30.

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More recently, the HEAT-PPCI trial, published in 2014, compared bivalirudin plus bailout GP IIb/IIIa inhibitors and heparin plus bailout GP IIb/IIIa inhibitors and showed reduced MACE (all-cause mortality, stroke, reinfarction, and target lesion revascularization) at 28 days in the heparin group with similar rates of bleeding. This trial increased use of heparin with likely more short-term GP IIb/IIIa inhibitor use31.

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The FDA approved an intravenous P2Y12 inhibitor, cangrelor, in June 2015. It is given as a bolus followed by a continuous infusion. Cangrelor has an immediate onset of antiplatelet effect and a plasma half-life of only 3 to 5 minutes that can be quickly reversed, unlike the GPIIb/IIIa inhibitors. In the CHAMPION PHOENIX trial, the use of GP IIb/IIIa inhibitor rescue therapy was significantly lower with a bolus and infusion of IV cangrelor than with a loading dose of 600mg or 300mg of clopidogrel in patients with coronary atherosclerosis who required PCI for stable angina, NSTE-ACS, or STEMI and who did not receive pretreatment with platelet inhibitors32. The approval of cangrelor will likely further decrease GP IIb/IIIa inhibitor usage in the future as less rescue therapy will be required during PCI. Also, cangrelor is a better alternative when a quicker offset is desired. Cangrelor was not studied in conjunction with GPIIb/IIIa inhibitors other than for rescue therapy and therefore, the FDA approved indication is as an adjunct to PCI in patients who are not being given a GP IIb/IIIa inhibitor.

ABCIXIMAB (REOPRO®) Abciximab was FDA approved in November 1997. It is an antigen-binding fragment (Fab) of a humanized murine monoclonal antibody 7E3 manufactured by Janssen Biologics BV and distributed by Eli Lilly under the trade name ReoPro®. It is a large molecule (47.6kDa) glycoprotein IIb/IIIa inhibitor with irreversible receptor inhibition. It binds the activated receptor with high affinity and causes conformational changes that block large molecules from binding to the receptor. Maximum platelet effect is present within 10 minutes and is achieved when at least 80% of GP IIb/IIIa receptors are blocked. Abciximab can persist on the surface of platelets for up to 2 weeks, unlike eptifibatide and tirofiban which have reversible receptor inhibition and do not remain in circulation in the platelet bound state as long as abciximab. Platelet function returns to normal about 96 to 120 hours after discontinuation of the medication. It is not renally cleared and therefore does not need to be adjusted for renal dysfunction, which gives abciximab a niche patient population. Neither eptifibatide nor tirofiban are recommended in patients on hemodialysis. Unlike the other GPIIb/IIIa inhibitors, abciximab has non-specific binding. It targets a closely related receptor, αVβ3, found on platelets and vessel wall endothelial and smooth

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ACCEPTED MANUSCRIPT muscle cells, which binds vitronectin and a αMβ2, a leukocyte integrin. This binding gives abciximab anti-inflammatory and antiproliferative properties, but clinical implications are unclear2, 33.

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Like the other GP IIb/IIIa inhibitors, the main adverse effect of abciximab is bleeding, most commonly gastrointestinal hemorrhage. Five percent of patients receiving abciximab experience thrombocytopenia. Abciximab-induced thrombocytopenia usually occurs in the immediate hours after administration but can occur up to 16 days later. The plasma half-life is about 10 minutes, with a second phase half-life of about 30 minutes. Its effects on platelet functions can be seen for up to 48 hours after the termination of the infusion. The only known treatment for this is platelet transfusions, which may or may not be effective, as abciximab may bind to new platelets being transfused34.

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Abciximab is supplied as a vial requiring refrigeration. Each single use vial contains a clear, colorless, sterile, non-pyrogenic solution for intravenous use at a concentration of 2mg/mL of abciximab. The dose requires a single bolus of 0.25mg/kg followed by a 12 hour infusion at 0.125mcg/kg/min 17. The bolus can be drawn straight from the vial but the continuous infusion must be diluted in normal saline or dextrose 5% in water.

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Abciximab is FDA approved for patients undergoing PCI and patients with UA/NSTEMI pre-PCI. However, it is not FDA approved for medical stabilization of UA/NSTEMI. Abciximab should only be used in patient undergoing PCI. It decreases the incidence of ischemic complications35 and decreases the need for repeat coronary artery revascularization in the first month following the procedure36. It is not an appropriate agent for patients scheduled for emergency surgery because of the longer bleeding time (approximately 12 hours to normalize) 37.

EPTIFIBATIDE (INTEGRILIN®) Eptifibatide is a synthetic cyclical KGD-containing heptapeptide manufactured by Millennium Pharmaceuticals, and co-promoted by Schering-Plough/Essex. It was approved by the FDA in May 1998 and is derived from a protein found in the venom of a southeastern pygmy rattlesnake (Sistrurus miliarius barbouri). Eptifibatide is a small molecule (0.832kDa) GP IIb/IIIa inhibitor with reversible receptor inhibition similar to tirofiban. It cannot be reversed with platelet infusions but the effects dissipate within 4 to 8 hours, with a half-life of about 2.5 hours2. This is the third GPIIb/IIIa inhibitor to enter the global market after abciximab and tirofiban. Eptifibatide comes as a pre-mixed vial requiring refrigeration. It cannot be stored outside of the refrigerator for longer than two months. The FDA approved dosing requires a double bolus (180mcg/kg each) ten minutes apart and then an infusion

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ACCEPTED MANUSCRIPT of 2mcg/kg/min up to 18-24 hours (with a minimum of 12 hours). It is approximately 50% renally cleared and therefore the dose needs to be adjusted for renal dysfunction and is contraindicated in patients on hemodialysis.

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Eptifibatide is FDA approved to reduce the risk of acute cardiac ischemic events (death and/or MI) for PCI, coronary stents, UA/NSTEMI pre-PCI, and for medical stabilization of UA/NSTEMI.

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TIROFIBAN (AGGRASTAT®)

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Tirofiban is a synthetic nonpetide tyrosine derivative that acts as an RGD (arginine-glycine-aspartic acid) mimetic. It is a small molecule (0.495kDa) GP IIb/IIIa inhibitor with reversible receptor inhibition. It has a high specificity for the GPIIb/IIIa receptor and a long plasma half-life of about 2 hours. The plateletbound half-life is short (seconds) and platelet function returns upon discontinuation within 4 to 8 hours. Tirofiban is about 65% renally cleared. It is not reversible with platelet infusions but its effect dissipates within 4 to 8 hours 2.

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In 1998, Merck launched the production of tirofiban. The PRISM38 and PRISMPLUS39 trials lead to FDA’s approval of the medication in 1998, evaluating a dosing regimen of 0.4mcg/kg/min for 30 minutes, followed by 0.10mcg/kg/min. Patients received tirofiban plus UFH or UFH. PRISM-PLUS was the landmark clinical trial that lead to tirofiban’s FDA approval40. It evaluated the original dosing regimen in the upstream setting and showed significantly lower mortality and rate of MI than with heparin alone. Because of this trial, tirofiban was rapidly adopted as a treatment for acute coronary syndrome (ACS) and became the most widely used small molecule GP IIb/IIa inhibitor from 1998 to 2000. Tirofiban was utilized for ACS until the TARGET trial missed its primary endpoint in 2001. In the TARGET trial, a 10mcg/kg bolus proved 61-66% IPA at 15 to 45 minutes versus 90-94% IPA with abciximab. Tirofiban was inferior in overall efficacy11. Multiple studies around this time showed less platelet inhibition with the low-dose bolus of tirofiban compared to the other GPIIb/IIIa inhibitors, which caused eptifibatide use to surpass tirofiban. Merck dropped the drug and it changed hands through a few different companies in the United States. In 2006, the Canadian company Medicure purchased tirofiban. The TENACITY trial (published in 2011) studied the use of tirofiban with a larger loading dose of 25mcg/kg bolus to obtain optimal early platelet inhibition 41. The high dose bolus regimen, consisting of 25mcg/kg bolus over 3 minutes followed by a 0.15mcg/kg/min infusion for up to 18 hours, at the time of PCI was approved in Europe in 2010. It achieves greater than 90% inhibition of platelet aggregation within 10 minutes. In patients with renal insufficiency (CrCl≤60mL/min), the dose is reduced to 25mcg/kg over 3 minutes followed by a 0.075mcg/kg/min infusion.

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The MULTISTRATEGY study (2008) compared high-dose bolus tirofiban to abciximab in patients with STEMI who received aspirin and clopidogrel up front and then were randomized to either tirofiban or abciximab and either a bare metal stent or a sirolimus-eluting stent. Both groups showed equivalent efficacy, similar safety/bleeding profiles, and similar overall mortality. Rates of moderate to severe thrombocytopenia were significantly higher with abciximab than with tirofiban42.

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The ACUITY trial (2006) analyzed more than 4,000 patients treated with upstream GP IIb/IIIa inhibitor. The substudy showed similar outcomes with upstream tirofiban and eptifibatide as a part of an early invasive management strategy in moderate- and high-risk ACS patients. The primary outcomes included 30-day rates of major adverse cardiac events (MACE) defined as death, myocardial infarction, or target vessel revascularization, non-CABG major bleeding, and net clinical outcomes (NACE)43, 44.

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A meta-analysis looked at 31 randomized controlled trials which included 20,006 patients. This showed similar efficacy between tirofiban and abciximab using surrogate markers such as TIMI-3 flow or ST-segment resolution, or hard outcomes like reinfarction or death45. Real-world registry data shows similar findings.

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In 2012 the ongoing SAVI-PCI study was announced, which is comparing tirofiban’s use as a high-dose bolus followed by a shortened infusion duration to the label-dosing in patients undergoing PCI46. This is also the year that a supplemental new drug application (sNDA) was prepared. The high-dose bolus (HDB) regimen of tirofiban was approved by the FDA in 2013, which achieves therapeutic platelet inhibition faster than with the original dosing regimen. Aggrastat® continues to be the number 1 used GPIIb/IIIa inhibitor worldwide. Tirofiban has the fewest FDA approved indications because it fell out of favor for several years due to the inferiority of the original dosing regimen. Because its owndership has moved through several companies throughout the years before finding the most effective dosing regimen, the sales force in the United States has been negligible until recently. It is only FDA approved for medical stabilization of UA/NSTEMI, gaining FDA approval in October 2013. For use during PCI, high dose tirofiban may be used as an alternative to other GP IIb/IIIa antagonists. The ACC/AHA NSTE-ACS guidelines7 and the ACC/AHA PCI guidelines9 both give tirofiban high dose bolus (HDB) regimen a class I recommendation. Current practice guidelines from the ACC, AHA, and ESC support the upstream use of GP IIb/IIIa inhibitors in high-risk patients with ACS managed by an invasive strategy. No preference is given to any of the agents. Tirofiban is supplied as pre-mixed IV bags (250mL and 100mL) at a concentration of 50mcg/mL manufactured by Baxter (Marion, NC) that can be

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ACCEPTED MANUSCRIPT stored at room temperature and is dosed as a single bolus with an infusion up to 18 hours.

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CLINICAL TRIALS

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The first major trial that tested the antithrombotic effects of GP IIb/IIIa inhibitors was the EPIC trial in 1994, which looked at the use of abciximab during high-risk balloon angioplasty in patients with unstable angina, evolving MI, or high risk angiographic lesions. Abciximab was shown to significantly reduce the composite risk of death, MI, recurrent ischemia, or failed reperfusion at 30 days. However, it did increase bleeding35. The EPILOG trial in 1997 built upon the EPIC trial, expanding the patient population to both elective and non-elective PCI. Abciximab significantly reduced death, MI, and urgent revascularization. It also showed that when abciximab was combined with lower-dose heparin (targeting an ACT >200 versus the then-standard target of >300), there were similar ischemic outcomes with lower bleeding complication rates47.

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Four trials included in what is known as the “4P” – PURSUIT39, PRISM38, PRISMPLUS40, and PARAGON48 – established the efficacy of GP IIb/IIIa inhibitors when added to medical therapy with aspirin and heparin for patients with NSTE-ACS. The PRISM-PLUS trial in 1998 compared tirofiban plus UFH with UFH alone and tirofiban alone in patients with NSTEMI given aspirin40. The group with tirofiban plus UFH showed superior outcomes to either alone. The tirofiban alone group was terminated early due to higher rates of mortality. The EPISTENT trial was designed to determine whether abciximab had benefits in PCI with stenting10. EPIC35 and EPILOG47 established abciximab as a standard of care in percutaneous transluminal coronary angioplasty (PTCA) without stenting. EPISTENT showed that stenting and GP IIb/IIIa inhibition have complimentary benefits and show increased longevity of event-free survival in PCI. At this point, several trials had shown that adding GPIIb/IIIa inhibitors to heparin and aspirin could reduce complications of PCI in patients with UA. The PURSUIT trial39 was the first major study to look at empiric GP IIb/IIIa inhibition in patients with NSTE-ACS rather than waiting on the determination of whether the patient would undergo revascularization. It showed that the empiric addition of eptifibatide to aspirin and UFH in NSTE-ACS improved ischemic outcomes. Because this study was published in 1998, this was prior to the era of upstream clopidogrel use, in which eptifibatide has shown to be more harmful than beneficial (EARLY ACS49). This trial in conjunction with later trials looking at clopidogrel use, began the utilization of dual antiplatelet therapy (aspirin plus clopidogrel, eptifibatide, or tirofiban).

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In 2001, the GUSTO IV-ACS trial attempted to broaden the usage of GPIIb/IIIa inhibitors but instead showed that abciximab did not confer any reduction in allcause mortality or MI at 30 days compared to placebo in patients with UA/NSTEMI managed conservatively and may be harmful50. It is for this reason that abciximab should not be initiated outside of catheterization lab or used in patients not undergoing PCI.

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In 2001, the TARGET trial was the first to compare the efficacy and safety of various GP IIb/IIIa inhibitors, looking specifically at abciximab versus tirofiban in patients undergoing PCI11. The results showed that abciximab was superior to tirofiban’s original dosing regimen, offering greater protection from major ischemic events.

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By 2004, giving a loading dose of clopidogrel 600mg to thienopyridine naïve patients prior to elective PCI was common practice. Previous trials, such as EPILOG47, showed that GP IIb/IIIa inhibition was beneficial in elective PCI, but this trial pre-dated the use of clopidogrel. The ISAR REACT 1 trial was designed to determine whether using abciximab in addition to clopidogrel was safe and effective in elective PCI. It showed that abciximab was not beneficial if clopidogrel 600mg was given at least 2 hours before the procedure51.

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The ISAR REACT 2 trial addressed patients undergoing PCI for NSTE-ACS, using almost the same design as ISAR REACT 1. It showed that in this patient population, abciximab was beneficial even if clopidogrel 600mg was given upstream52. Therefore, the benefits of abciximab in PCI after clopidogrel administration are confined to patients presenting with STEMI and high-risk NSTE-ACS. In 2006, the ACUITY trial compared the use of bivalirudin with the combination of UFH or low molecular weight heparin (LMWH) with a GP IIb/IIIa inhibitor in moderate- to high-risk NSTEMI patients receiving clopidogrel and aspirin before PCI. This trial showed that bivalirudin was as effective as the combination therapy and caused less bleeding44, 53. This trial led to the ACC/AHA guideline recommendation stating that it may be reasonable to omit GP IIb/IIIa inhibitors in NSTEMI patients who receive bivalirudin and alternative dual-antiplatelet therapy7. Then, in 2008, authors of HORIZONS-AMI compared bivalirudin to a combination of heparin with a GP IIb/IIIa inhibitor in patients undergoing PCI for STEMI, showing that bivalirudin decreased mortality at 30 days28. Therefore, bivalirudin became the agent of choice in this setting. It is given a Class IIa recommendation over UFH with a GP IIb/IIIa inhibitor for PCI in patients at highrisk of bleeding, including older patients7. The EARLY-ACS trial in 2009, attempted to discern the optimal timing of GP IIb/IIIa inhibitors, using eptifibatide along with aspirin and clopidogrel both

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upstream (prior to angiography) and deferred (as needed based on angiography) in UA/NSTEMI patients. It showed that triple antiplatelet therapy upstream resulted in higher bleeding rates without reducing ischemic endpoints49, 54.

CONCLUSIONS

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The benefits of GP IIb/IIIa inhibitors are greatest when use in patients with large intracoronary thrombus burdens undergoing PCI. The optimal duration of infusion of GP IIb/IIIa inhibitors is still being evaluated. While each of the commercially available GP IIb/IIIa inhibitors has differences in structure and pharmacodynamics that make its utilization unique, they all are use for the same general indications. These subtle differences come into play when taking into account patient specific factors, such as renal dysfunction and timing with regards to percutaneous or potential surgical intervention. The large-molecule GP IIb/IIIa inhibitor abciximab has a longer clearance time of 12 to 24 hours while smaller molecule eptifibatide and tirofiban have clearance times of only 2 to 2.5 hours, making them more desirable when reversal may be necessary, such as in the circumstance of a potential cardiac surgery37. The small molecule inhibitors are renally eliminated and therefore must be dose adjusted in chronic kidney disease, making them imperfect choices in this patient population. Eptifibatide requires a second bolus 10 minutes after the first bolus, which can be a detracting factor from the medication. It also must be stored in the refrigerator while tirofiban can be stored at room temperature. While tirofiban fell out of favor in the United States after the original dosing regimen proved to be inferior to other GP IIb/IIIa inhibitors, the newer high-dose bolus regimen of tirofiban has resulted in tirofiban being the most highly utilized GP IIb/IIIa inhibitor in Europe. New dosing recommendations make tirofiban equally as effective as both abciximab and eptifibatide for treatment of UA and NSTEMI. Efficacy data from clinical trials and real world registry data show similar outcomes including mortality, target vessel revascularization, and bleeding with high-dose tirofiban compared to other GP IIb/IIIa inhibitors.

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Graphical abstract

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